A functional gastrointestinal system is dependent on the enteric nervous system, which is formed during embryogenesis through colonization of the gut by enteric neural crest cells (ENCCs). Now, Niswander and colleagues identify the protein phosphatase 1 (PP1)- and actin-binding protein Phactr4 as a regulator of directional and collective ENCC migration (Genes Dev. 26, 69–81; 2012).

Analysis of mouse embryos expressing a Phactr4 mutation known to abolish PP1 binding revealed reduced enteric neuronal numbers and defective organization at embryonic day 18.5, and reduced ENCC numbers in the gut at earlier stages (E12.5). These defects were not due to defective ENCC specification, proliferation or differentiation. Instead, time-lapse imaging of hindgut organ explants revealed disrupted directional migration of ENCCs and detachment of cells from the wave front. Inhibition of PP1 caused similar migration defects in wild-type organ cultures. In wound healing assays, mutant mouse embryonic fibroblasts (MEFs) displayed randomized actin protrusion and migration directions, and reduced lamellipodia size. Phactr4 co-localized with the actin regulator cofilin and integrin-β1 at lamellipodia tips, and mutant cells displayed a ROCK-kinase-dependent increase in phosphorylation of cofilin and increased integrin-β1 signalling. Interestingly, inhibition of integrin signalling or ROCK activity rescued directed migration of MEFs and normalized the migration of ENCCs in organ cultures. Although the precise function of Phactr4 remains to be discovered, these data demonstrate its role in regulating lamellipodial actin dynamics through cofilin activity controlled by integrin and PP1 signalling.